DESCRIPTION (Verbatim from the Applicant's Abstract): Although cell migration is an essential step in neural development, our understanding of mechanisms underlying neuronal migration is still limited. This application focuses on cellular and molecular mechanisms guiding the direction of migratory neurons in the mammalian brain. In preliminary studies, we have demonstrated that the Slit family of secreted proteins can act as repulsive cues for migrating neurons. Together with previous findings by us and others that Slit is a chemorepellent for projecting axons, these results suggest that some mechanisms may be shared between axon guidance and neuronal migration. The availability of a guidance molecule for neuronal migration provides a foundation for our future studies of neuronal migration. We will dissect the functional domains of Slit and its receptor Robo to reveal whether the same domains are involved in axon guidance and neuronal migration. We will examine the roles of endogenous Slit in neuronal migration and axon guidance by using inhibitors. We will investigate subcellular and molecular components mediating the response of neurons to Slit. To reveal the role of specific Slit genes in neuronal migration and possibly in other developmental processes, we will use gene targeting to create a loss of function mutation in mouse Slit3 gene and analyze its consequences. The proposed experiments with interdisciplinary approaches should contribute to further understanding of the molecular mechanisms of neuronal migration.